OVARIAN PRIMORDIAL FOLLICLE DEVELOPMENT The proposed research is directed toward developing a better understanding of the mechanisms that control primordial follicle development. This process is essential for the establishment and maintenance of female reproduction. Primordial follicle development involves the initial event of primordial follicle assembly and the subsequent event of primordial to primary follicle transition. The process involved in primordial follicle assembly is distinct from that of primordial to primary follicle transition and both will be investigated in the proposed research. The manner by which locally produced ovarian substances and hormones regulate these processes are of particular interest. Previous research and preliminary studies have demonstrated that the control of primordial follicle development and subsequent folliculogenesis appears to be mediated by the local production and action of specific paracrine factors involving theca cells, granulosa cells, and the oocyte. Preliminary studies have shown that steroid hormones (i.e. estrogen and progesterone) play a critical role in the onset of primordial follicle assembly. Preliminary studies also demonstrate that primordial to primary follicle transition requires integrated interactions between the oocyte, granulosa cells and precursor theca cells involving kit ligand (KL),basic fibroblast growth factor (bFGF), leukemia inhibitory factor (LIF), keratinocyte growth factor (KGF) and bone morphogenic protein-4 (BMP4). "THE GENERAL HYPOTHESIS TESTED IS THAT HORMONES INFLUENCE THE PARACRINE GROWTH FACTOR MEDIATED INTERACTIONS BETWEEN THE OVARIAN SOMATIC CELLS AND THE OOCYTE TO CONTROL PRIMORDIAL FOLLICLE ASSEMBLY AND DEVELOPMENT". Interactions between hormones and paracrine growth factors provide an efficient mechanism to control primordial follicle development. It is anticipated that abnormalities in these cellular interactions will influence female fertility, menopause onset and promote pathophysiologies such as premature ovarian failure. The experimental approach consists of the following specific aims: 1) Elucidate the hormonal and paracrine growth factor control of primordial follicle assembly. 2) Elucidate the hormonal and growth factor control of the primordial to primary follicle transition. 3) Elucidate the physiological importance of specific factors that mediate primordial follicle development. Completion of these specific aims will extend previous observations and provide insight into the role of growth factor mediated cell-cell interactions in regulating primordial follicle development. The critical developmental periods to be examined include the induction of primordial follicle assembly and the primordial to primary follicle transition. It is anticipated that the specific cell-cell interactions will change between these developmental periods. The differential effects of hormones on growth factors and relevant receptors have a critical role in later stages of follicle development, but remain to be determined in primordial follicle development. Observations are anticipated to provide insight into the molecular and cellular control of primordial follicle development. PUBLIC HEALTH RELEVANCE: The information obtained will be used to understand the onset of puberty and menopause, as well as provide insight into the potential future design of diagnostic procedures and therapeutic treatments for abnormal ovarian conditions such as premature ovarian failure (POF) and forms of female infertility. An example of a future experiment proposed is to determine if mutation(s) exist in any of the repertoire of growth factors and/or receptors established in the current study as potential causal factors for disease states such as premature ovarian failure.